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Mechanism of the persistent sodium current activator veratridine‐evoked Ca 2+ elevation: implication for epilepsy
Author(s) -
Fekete Ádám,
Franklin Laura,
Ikemoto Takeshi,
Rózsa Balázs,
Lendvai Balázs,
Sylvester Vizi E.,
Zelles Tibor
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06368.x
Subject(s) - veratridine , biophysics , depolarization , chemistry , endoplasmic reticulum , extracellular , glutamate receptor , epileptogenesis , tetrodotoxin , activator (genetics) , hippocampal formation , intracellular , ionotropic effect , reversal potential , sodium , sodium channel , endocrinology , biochemistry , receptor , biology , patch clamp , organic chemistry
Although the role of Na + in several aspects of Ca 2+ regulation has already been shown, the exact mechanism of intracellular Ca 2+ concentration ([Ca 2+ ] i ) increase resulting from an enhancement in the persistent, non‐inactivating Na + current ( I Na,P ), a decisive factor in certain forms of epilepsy, has yet to be resolved. Persistent Na + current, evoked by veratridine, induced bursts of action potentials and sustained membrane depolarization with monophasic intracellular Na + concentration ([Na + ] i ) and biphasic [Ca 2+ ] i increase in CA1 pyramidal cells in acute hippocampal slices. The Ca 2+ response was tetrodotoxin‐ and extracellular Ca 2+ ‐dependent and ionotropic glutamate receptor‐independent. The first phase of [Ca 2+ ] i rise was the net result of Ca 2+ influx through voltage‐gated Ca 2+ channels and mitochondrial Ca 2+ sequestration. The robust second phase in addition involved reverse operation of the Na + –Ca 2+ exchanger and mitochondrial Ca 2+ release. We excluded contribution of the endoplasmic reticulum. These results demonstrate a complex interaction between persistent, non‐inactivating Na + current and [Ca 2+ ] i regulation in CA1 pyramidal cells. The described cellular mechanisms are most likely part of the pathomechanism of certain forms of epilepsy that are associated with I Na,P . Describing the magnitude, temporal pattern and sources of Ca 2+ increase induced by I Na,P may provide novel targets for antiepileptic drug therapy.